Apoptosis (programmed cell death) is common to all multicellular organisms. Apoptosis plays a central role in cell differentiation, removal of damaged cells, and the homeostasis of the immune system. There are two apoptosis signal pathways: the extrinsic (transmitted through death receptors (DR)) or the intrinsic (mitochondrial) death pathways. A death receptor, CD95 (Fas/APO-1), was discovered 20 years ago. This review is focused on the mechanisms of death receptor-induced apoptosis via CD95 (Fas/APO-1)-mediated apoptosis and the role of the antiapoptotic protein c-FLIP in the extrinsic apoptosis regulation. The regulation of this pathway is crucial for the immune system. Defects in the regulation of CD95-mediated result in serious diseases such as cancer, autoimmunity, and AIDS. Therefore, gaining insights into apoptosis will have wide implications for developing approaches to treatment strategies of these diseases.